U.S. patent number 4,455,307 [Application Number 06/455,780] was granted by the patent office on 1984-06-19 for antihypertensive use of triazolobenzodiazepines.
This patent grant is currently assigned to The Upjohn Company. Invention is credited to Jackson B. Hester, Jr..
United States Patent |
4,455,307 |
Hester, Jr. |
June 19, 1984 |
**Please see images for:
( Certificate of Correction ) ** |
Antihypertensive use of triazolobenzodiazepines
Abstract
This specification concerns the use to treat hypertension in
mammals of novel and known
4H-s-triazolo[4,3-a][1,4]benzodiazepines, known
4H-s-triazolo[4,3-a][1,3,4]benzotriazepines and
2,4-dihydro-2-alkyl-1H-s-triazolo[4,3-a][1,4]benzodiazepin-1-ones,
and novel
2,4-dihydro-2-alkyl-1H-s-triazolo[4,3-a][1,4]benzodiazepin-1-thiones.
Inventors: |
Hester, Jr.; Jackson B.
(Comstock Township, Kalamazoo County, MI) |
Assignee: |
The Upjohn Company (Kalamazoo,
MI)
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Family
ID: |
26990387 |
Appl.
No.: |
06/455,780 |
Filed: |
January 5, 1983 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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336814 |
Jan 4, 1982 |
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Current U.S.
Class: |
514/220;
540/564 |
Current CPC
Class: |
C07D
498/04 (20130101); A61K 31/55 (20130101) |
Current International
Class: |
A61K
31/55 (20060101); C07D 498/04 (20060101); C07D
498/00 (20060101); A61K 031/55 (); C07D
487/04 () |
Field of
Search: |
;260/243.3,245.5,244.4
;424/246,248.4,248.5,248.52,248.58,250,263,267,269 |
References Cited
[Referenced By]
U.S. Patent Documents
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3646055 |
February 1972 |
Hester, Jr. |
3709899 |
January 1973 |
Hester, Jr. |
3734922 |
May 1973 |
Hester, Jr. |
3751426 |
August 1973 |
Hester, Jr. |
3767660 |
October 1973 |
Hester, Jr. |
3786149 |
January 1974 |
Collins |
3803315 |
April 1974 |
Collins |
3821388 |
June 1974 |
Collins |
3836660 |
September 1974 |
Collins |
3836661 |
September 1974 |
Collins |
3840664 |
October 1974 |
Collins |
3856802 |
December 1974 |
Szmuszkovicz |
3864356 |
February 1975 |
Meguro et al. |
3865811 |
February 1975 |
Meguro et al. |
3870706 |
March 1975 |
Allgeier et al. |
3880877 |
April 1975 |
Sellstedt et al. |
3882101 |
May 1975 |
Sellstedt |
3886174 |
May 1975 |
Hester, Jr. |
3891666 |
June 1975 |
Hester, Jr. |
3894025 |
July 1975 |
Hester, Jr. |
3912753 |
October 1975 |
Hester, Jr. |
3987052 |
October 1976 |
Hester, Jr. |
3996230 |
December 1976 |
Hester, Jr. |
4000289 |
December 1976 |
Collins |
4141902 |
February 1979 |
Hester, Jr. |
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Foreign Patent Documents
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51-6994 |
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Jan 1976 |
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JP |
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1323277 |
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Jul 1973 |
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GB |
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1331015 |
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Sep 1973 |
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GB |
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Other References
The Merck Veterinary Manual, 5th Ed., Merck and Co., Rahway, N.J.,
1979, p. 59. .
Comer and Matier In Burger's Medicinal Chemistry, 4th Ed., Part
III, John Wiley and Sons Inc., New York, 1981, pp. 285-337. .
Chai et al., J. Pharm. Exp. Ther. 154:271 (1966). .
Anonymous, Med. Lett. Drug Therap. 16:96 (1974). .
Whitehead, et al., Biol. Psych. 12:597 (1977). .
D. Kelly, "Clinical Experience with Benzodiazepines in
Psychosomatic Disorders," In R. G. Priest et al., Eds.,
Benzodiazepines Today and Tomorrow, University Park Press,
Baltimore, Md. 1980, pp. 99-112. .
Rudzik and Kamdar, J. Med. Chem. 14:1078 (1971). .
Hester and VonVoigtlander, J. Med. Chem. 22:1390 (1979). .
Hester, Rudzik and VonVoigtlander, J. Med. Chem. 23:392 (1980).
.
Hester, Rudzik and VonVoigtlander, J. Med. Chem. 23:402
(1980)..
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Primary Examiner: Raymond; Richard
Attorney, Agent or Firm: Welch; Lawrence T. Armitage; Robert
A. Scanlon; William G.
Parent Case Text
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a continuation-in-part of application Ser. No.
336,814, filed Jan. 4, 1982, now abandoned.
Claims
I claim:
1. A method of treating hypertension in mammals which comprises
administering to a mammal suffering from said disease an amount of
a compound of formula I
wherein
(1)-A-(2) is (1)--CR.sub.1 .dbd.N--(2) or
(1)--C(.dbd.X.sub.1)--NR.sub.11 --(2);
wherein
R.sub.1 is
(a) hydrogen;
(b) alkyl of 1 to 6 carbon atoms;
(c) chlorine, bromine or iodine;
(d) --CHX.sub.2 X.sub.3 wherein X.sub.2 is halogen; and X.sub.3,
being the same as or different from X.sub.2, is hydrogen, methyl,
ethyl, fluorine, chlorine, or bromine;
(e) trifluoromethyl;
(f) cyano or cyanomethyl;
(g) --X.sub.4 R.sub.12, wherein X.sub.4 is oxygen or sulfur, and
R.sub.12 is alkyl of 1 to 3 carbon atoms or --(CH.sub.2).sub.2
NR.sub.15 R.sub.16, wherein R.sub.15 and R.sub.16 are the same or
different and are hydrogen or methyl;
(h) --CH.sub.2 X.sub.4 R.sub.13, wherein R.sub.13 is hydrogen or
alkyl of 1 to 3 carbon atoms, inclusive;
(i) 3-pyridyl;
(j) azetidino, pyrrolidino or piperidino;
(k) pyrrolidinomethyl;
(l) 4-methyl-1-piperazinyl; or
(m) c--N(CH.sub.2 CH.sub.2).sub.2 X.sub.4 ;
wherein
R.sub.11 is methyl or ethyl; and
wherein
X.sub.1 is oxygen or sulfur;
wherein
B is --CHR.sub.4 -- or --NH--, wherein R.sub.4 is hydrogen or
methyl;
wherein
R.sub.6 is
(a) phenyl;
(b) phenyl substituted at 1 or 2 positions with halogen, wherein,
if disubstituted, the substituents are the same or different;
or
(c) 2-pyridyl; and
wherein
R.sub.8 is hydrogen, halogen, or --X.sub.8 R.sub.81, wherein
X.sub.8 is sulfur, sulfinyl or sulfonyl and R.sub.81 is alkyl of 1
to 3 carbon atoms; with the provisos that
(i) R.sub.1 is c--N(CH.sub.2 CH.sub.2).sub.2 X.sub.4 and R.sub.6 is
phenyl only when R.sub.8 is other than hydrogen;
(ii) R.sub.1 is pyrrolidino only when R.sub.8 is other than bromo
or iodo;
(iii) R.sub.1 is methyl, B is CHR.sub.4 and R.sub.4 is hydrogen
only when
(a) R.sub.8 is other than --SR.sub.81, and
(b) R.sub.6 is other than phenyl, o-fluorophenyl,
2,5-difluorophenyl, 2-chloro-5-fluorophenyl, or o-chlorophenyl;
(iv) R.sub.1 is hydrogen, ethyl, n-propyl or isopropyl, and B is
--CHR.sub.4 ; or R.sub.1 is methyl, B is --CHR.sub.4, and R.sub.4
is methyl, only when
(a) R.sub.8 is other than --SR.sub.81, and
(b) R.sub.6 is other than phenyl; and
(v) R.sub.1 is n-butyl, n-pentyl, n-hexyl or isomers thereof only
when R.sub.8 is other than SR.sub.81 ; and
(vi) B is --NH-- only when
(a) A is --CR.sub.1 .dbd.N--,
(b) R.sub.1 is hydrogen or alkyl of 1 to 6 carbon atoms, and
(c) R.sub.6 is other than 2-pyridyl;
or a pharmacologically acceptable acid addition salt thereof,
effective to lower the mammal's systemic arterial blood
pressure.
2. A method according to claim 1 wherein the compound is one in
which A is --CR.sub.1 .dbd.N--; B is --CHR.sub.4 --; R.sub.4 is
hydrogen; R.sub.1 is methyl, ethyl, n-propyl, chlorine, bromine,
iodine, methoxy, ethoxy, methylthio, ethylthio, n-propylthio,
3-pyridyl, morpholino or thiomorpholino; R.sub.8 is hydrogen or
halogen; and R.sub.6 is phenyl, o-chlorophenyl, p-chlorophenyl or
2-pyridyl, with the provisos that R.sub.1 is methyl only when
R.sub.6 is other than phenyl or o-chlorophenyl and R.sub.1 is ethyl
or n-propyl only when R.sub.6 is other than phenyl.
3. A method according to claim 1 wherein the compound is one in
which B is --NH--; R.sub.1 is methyl; R.sub.8 is chlorine, bromine
or iodine; and R.sub.6 is phenyl, o-chlorophenyl or
p-chlorophenyl.
4. A method according to claim 1 wherein the compound is one in
which A is --C(.dbd.X.sub.1)--NR.sub.11 --; R.sub.11 is methyl or
ethyl; R.sub.8 is hydrogen or halogen; and R.sub.6 is phenyl,
o-chlorophenyl, p-chlorophenyl or 2-pyridyl.
5. A method according to claim 2 wherein the compound is one of the
group comprising the 4H-s-triazolo[4,3-a][1,4]benzodiazepines of
formula II ##STR2## defined as follows, or a pharmacologically
acceptable acid addition salt thereof:
6. A method according to claim 3 wherein the compound is one of the
group comprising
8-chloro-1-methyl-6-phenyl-4H-s-triazolo1[4,3-a][1,3,4]benzotriazepine,
8-bromo-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,3,4]benzotriazepine,
and
8-iodo-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,3,4]benzotriazepine,
or a pharmacologically acceptable acid addition salt thereof.
7. A method according to claim 4 wherein the compound is one in
which X.sub.1 is oxygen.
8. A method according to claim 4 wherein the compound is one in
which X.sub.1 is sulfur.
9. A method according to claim 7 wherein the compound is one of the
group comprising
8-chloro-2,4-dihydro-2-methyl-6-phenyl-1H-s-triazolo[4,3-a][1,4]benzodiazep
in-1-one,
8-bromo-2,4-dihydro-2-methyl-6-phenyl-1H-s-triazolo[4,3-a]-[1,4]benzodiazep
in-1-one,
8-iodo-2,4-dihydro-2-methyl-6-phenyl-1H-s-triazolo[4,3-a]-[1,4]benzodiazepi
n-1-one,
8-chloro-2,4-dihydro-2-ethyl-6-phenyl-1H-s-triazolo[4,3-a]-[1,4]benzodiazep
in-1-one,
8-bromo-2,4-dihydro-2-ethyl-6-phenyl-1H-s-triazolo[4,3-a]-[1,4]benzodiazepi
n-1-one, and
8-iodo-2,4-dihydro-2-ethyl-6-phenyl-1H-s-triazolo[4,3-a]-[1,4]benzodiazepin
-1-one,
or a pharmacologically acceptable acid addition salt thereof.
10. A method according to claim 8 wherein the compound is one of
the group comprising
8-chloro-2,4-dihydro-2-methyl-6-phenyl-1H-s-triazolo[4,3-a]-[1,4]benzodiaze
pin-1-thione,
8-bromo-2,4-dihydro-2-methyl-6-phenyl-1H-s-triazolo[4,3-a]-[1,4]benzodiazep
in-1-thione,
8-iodo-2,4-dihydro-2-methyl-6-phenyl-1H-s-triazolo[4,3-a]-[1,4]benzodiazepi
n-1-thione,
8-chloro-2,4-dihydro-2-ethyl-6-phenyl-1H-s-triazolo[4,3-a]-[1,4]benzodiazep
in-1-thione,
8-bromo-2,4-dihydro-2-ethyl-6-phenyl-1H-s-triazolo[4,3-a]-[1,4]benzodiazepi
n-1-thione, and
8-iodo-2,4-dihydro-2-ethyl-6-phenyl-1H-s-triazolo[4,3-a]-[1,4]benzodiazepin
-1-thione,
or a pharmacologically acceptable acid addition salt thereof.
11. A compound of formula III ##STR3## wherein (1)-D-(2) is
(1)--C(c--N(CH.sub.2 CH.sub.2).sub.2 S).dbd.N--(2), or
(1)--C(c--N(CH.sub.2).sub.3).dbd.N--(2),
wherein
R.sub.14 is hydrogen or methyl;
wherein
R.sub.116 is
(a) phenyl;
(b) phenyl substituted at 1 or 2 positions with halogen wherein, if
disubstituted, the substituents are the same or different; or
(c) 2-pyridyl; and
wherein
R.sub.118 is hydrogen, halogen or --X.sub.9 R.sub.91, wherein
X.sub.9 is sulfur, sulfinyl, or sulfonyl and R.sub.91 is alkyl of 1
to 3 carbon atoms; with the proviso that (1)-D-(2) is
(1)--C(c--N(CH.sub.2 CH.sub.2).sub.2 S).dbd.N--(2) and R.sub.116 is
phenyl only when R.sub.118 is other than hydrogen;
or a pharmacologically acceptable acid addition salt thereof.
12. A compound according to claim 11 wherein (1)-D-(2) is
(1)--C(c--N(CH.sub.2 CH.sub.2).sub.2 S).dbd.N--(2), R.sub.114 is
hydrogen, R.sub.116 is phenyl, o-chlorophenyl, p-chlorophenyl or
2-pyridyl, and R.sub.118 is hydrogen or halogen, with the proviso
that, when R.sub.116 is phenyl, R.sub.118 is other than
hydrogen.
13. A compound according to claim 11 wherein (1)-D-(2) is
(1)--C(c--N(CH.sub.2).sub.3).dbd.N--(2), R.sub.114 is hydrogen,
R.sub.116 is phenyl, o-chlorophenyl, p-chlorophenyl or 2-pyridyl,
and R.sub.118 is hydrogen or halogen.
14. A compound according to claim 12 selected from the group
comprising the
1-thiomorpholino-4H-s-triazolo[4,3-a][1,4]-benzodiazepines of
formula XVI ##STR4## defined as follows, or a pharmacologically
acceptable acid addition salt thereof:
15. A compound according to claim 13 selected from the group
comprising the 1-azetidino-4H-s-triazolo[4,3-a][1,4]benzodiazepines
of formula XVII ##STR5## defined as follows, or a pharmacologically
acceptable acid addition salt thereof:
16. A compound according to claim 14 selected from the group
comprising
8-chloro-6-phenyl-1-thiomorpholino-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine
8-bromo-6-phenyl-1-thiomorpholino-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine,
and
8-iodo-6-phenyl-1-thiomorpholino-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine,
or a pharmacologically acceptable acid addition salt thereof.
17. A compound according to claim 15 selected from the group
comprising
8-chloro-6-phenyl-1-azetidino-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine,
8-bromo-6-phenyl-1-azetidino-4H-s-triazolo[4,3-a]-[1,4]-benzodiazepine,
and
8-iodo-6-phenyl-1-azetidino-4H-s-triazolo[4,3-a][1,4]-benzodiazepine,
or a pharmacologically acceptable acid addition salt thereof.
18. A method according to any of claims 1 to 10, inclusive, wherein
the mammal being treated is a human.
Description
DESCRIPTION
Technical Background
The present invention relates to a novel method of use for known
compounds. The present invention also relates to novel compounds
and their use in the same method of use discovered for the known
compounds.
In particular, the invention relates to the novel method of
lowering the blood pressures of mammals, including humans, by
administration thereto of sufficient amounts of certain known and
novel 4H-s-triazolo[4,3-a][1,4]benzodiazepines, certain known
4H-s-triazolo[4,3-a][1,3,4]-benzotriazepines and
2,4-dihydro-2-alkyl-1H-s-triazolo[4,3-a][1,4]-benzodiazepin-1-ones,
and certain novel
2,4-dihydro-2-alkyl-1H-s-triazolo[4,3-a][1,4]benzodiazepin-1-thiones,
or pharmacologically acceptable acid addition salts thereof.
The invention concerns, therefore, a method of treating
hypertension in mammals, including humans.
The invention also concerns novel
1-thiomorpholino-4H-s-triazolo[4,3-a][1,4]-benzodiazepines,
1-azetidino-4H-s-triazolo[4,3-a][1,4]benzodiazepines, and
2,4-dihydro-2-alkyl-1H-s-triazolo[4,3-a][1,4]benzodiazepin-1-thiones,
and their pharmacologically acceptable acid addition salts.
Hypertension is a disease characterized by pathologically elevated,
systemic arterial blood pressure. Hypertension in humans and agents
for treating the disease have recently been reviewed by Comer and
Matier in Burger's Medicinal Chemistry, 4th Ed., Part III, John
Wiley and Sons Inc., New York, 1981, pp. 285-337. Hypertension is
also known to occur in non-human mammals. See, e.g., the Merck
Veterinary Manual, 5th Ed., Merck and Co. Rahway, N.J., 1979, p.
59.
Ill effects caused or exacerbated by hypertension, in humans as
well as other mammals, include renal insufficiency and failure,
stroke, cardiac insufficiency and failure, and increased risks of
coronary and cerebral atherosclerosis and the untoward consequences
thereof. By reducing the blood pressure of a mammal suffering from
hypertension, the ill effects of the disease can be prevented,
ameliorated, or eliminated.
Numerous methods and agents for reducing blood pressure in mammals
are known. Methods and agents for reducing hypertension in humans
are reviewed in the Comer and Matier reference cited above. Most
methods and agents effective for reducing hypertension in humans
are also effective for reducing blood pressure in non-human
mammals, including those suffering from hypertension. Indeed, the
usefulness of a method or agent for treating hypertension in humans
is usually first indicated by its blood-pressure lowering effect in
non-human mammals.
Numerous agents active in the central nervous system are known to
be antihypertensives. Many of these centrally acting agents are
also active as hypnotics, sedatives, tranquilizers, or muscle
relaxants. See the Comer and Matier chapter, cited above, at pages
292-302.
There are indications that non-triazole-ring-bearing
benzodiazepines, such as diazepam and bromazepam, which are active
through the central nervous systems of mammals as, among others,
tranquilizers, muscle relaxants, sedatives, anxiolytics or
anticonvulsants, might also be active as antihypertensives in
mammals. See Chai et al., J. Pharm. Exp. Ther. 154, 271 (1966);
Anonymous, Med. Lett. Drug Therap. 16, 96 (1974); Whitehead et al.,
Biol. Psych. 12, 597 (1977); D. Kelly, "Clinical Experience with
Benzodiazepines in Psychosomatic Disorders," in R. G. Priest et
al., eds., Benzodiazepines Today and Tomorrow, University Park
Press, Baltimore, Md., 1980, pp. 99-112.
Known compounds of concern in the present specification are
disclosed in Hester, Rudzik and Kamdar, J. Med. Chem. 14, 1078
(1971); Hester and VonVoigtlander, J. Med. Chem. 22, 1390 (1979);
Hester, Rudzik and VonVoigtlander, J. Med. Chem. 23, 392 (1980);
and Hester, Rudzik and VonVoigtlander, J. Med. Chem. 23, 402
(1980); in the following U.S. Pat. Nos. 3,646,055; 3,709,899;
3,734,922; 3,751,426; 3,767,660; 3,856,802; 3,870,706; 3,880,877;
3,882,101; 3,886,174; 3,891,666; 3,894,025; 3,912,753; 3,987,052;
3,996,230; and 4,141,902; and in Belgian Pat. No. 782,680.
The known compounds are disclosed to be active as sedatives,
tranquilizers and muscle-relaxants in mammals and birds. See U.S.
Pat. Nos. 3,646,055; 3,734,922; 3,751,426; 3,767,660; 3,856,802;
3,880,877; 3,882,101; 3,886,174; 3,891,666; 3,894,025; 3,912,753;
3,987,052; 3,996,230; 4,141,902; see also Belgian Pat. No.
782,680.
The known compounds wherein the substituent at the 6-position is
2-pyridyl have additionally been disclosed to be hypnotics and
anticonvulsants in birds and mammals. See U.S. Pat. Nos. 3,734,922
and 3,767,660. Several of the known compounds are known to possess
anxiolytic activity in mammals. See U.S. Pat. Nos. 3,894,025;
3,912,753; and 3,996,230; and Hester, Rudzik and Kamdar; Hester and
VonVoigtlander, and both Hester, Rudzik and VonVoigtlander
references, all cited above. The known
2,4-dihydro-2-alkyl-1H-s-triazolo[4,3-a][1,4]benzodiazepin-1-ones
have been disclosed to have anti-aggressive-behavior effects in
mammals and birds. See U.S. Pat. No. 3,646,055. See also U.S. Pat.
No. 3,865,811, which discloses that
2,4-dihydro-1H-s-triazolo[4,3-a][1,4]benzodiazepin-1-ones and
-1-thiones unsubstituted at the nitrogen atom at position 2 are
anticonvulsants and sleep-inducers in mammals. The
1-(4-methyl-1-piperazinyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepines,
1-morpholino-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine
and 1-pyrrolidino-8-chloro-6-phenyl-4H-s-triazolo[
4,3-a][1,4]benzodiazepine display antidepressant activity in
mammals. U.S. Pat. Nos. 3,894,025 and 3,996,230; Hester and
VonVoigtlander, cited above; Hester, Rudzik and VonVoigtlander, J.
Med. Chem. 23, 392 (1980). 1-Aminoalkyloxy- and
1-aminoalkylthio-4H-s-triazolo[4,3-a][1,4]benzodiazepines have been
disclosed to be hypnotics and anticonvulsants in mammals and birds.
U.S. Pat. No. 3,912,753. 1-alkoxymethyl and
1-hydroxymethyl-4H-s-triazolo[4,3-a][1,4]benzodiazepines have been
disclosed to inhibit somatic reflexes and have depressant,
including anticonvulsant and anti-aggressive-behavior, effects in
mammals. U.S. Pat. No. 3,870,706. Other 6-(2-pyridyl) substituted
compounds are apparently disclosed in Japanese Kokai 6994/76,
Derwent Abstract No. 17551X.
Many of the known compounds have also been disclosed to be useful
for increasing the growth rate, productivity and feed-utilization
efficiency of meat-producing, milk-producing or egg-laying farm
animals. See U.S. Pat. Nos. 3,734,922; 3,767,660; 3,786,149;
3,803,315; 3,821,388; 3,836,660; 3,836,661; 3,840,664; 3,856,802;
and 4,000,289.
1-Morpholino-, 1-piperazino-, 1-piperidino-, 1-pyrrolidino, and
1-(4H-1,4-thiazin-4-yl)-4H-s-triazolo[4,3-a][1,4]benzodiazepines
substituted at the 6-position and optionally substituted at the 4-
and 8-positions have been disclosed. U.S. Pat. Nos. 3,709,899;
3,767,660; 3,894,025 and 3,996,230; and British Pat. No.
1,323,277.
2,4-Dihydro-1H-s-triazolo[4,3-a][1,4]benzodiazepin-1-thiones
substituted with optionally substituted phenyl at the 6-position,
optionally substituted at the 4- and 8-positions, and unsubstituted
at the 2-position are known. U.S. Pat. Nos. 3,864,356 and
3,865,811.
SUMMARY OF THE INVENTION
The present invention provides
(A) A method of treating hypertension in mammals which comprises
administering to a mammal suffering from said disease an amount of
a compound of formula I
wherein
(1)-A-(2) is (1)--CR.sub.1 .dbd.N--(2) or
(1)--C(.dbd.X.sub.1)--NR.sub.11 -(2);
wherein
R.sub.1 is
(a) hydrogen;
(b) alkyl of 1 to 6 carbon atoms;
(c) chlorine, bromine or iodine;
(d) --CHX.sub.2 X.sub.3 wherein X.sub.2 is halogen; and X.sub.3,
being the same as or different from X.sub.2, is hydrogen, methyl,
ethyl, fluorine, chlorine, or bromine;
(e) trifluoromethyl;
(f) cyano or cyanomethyl;
(g) --X.sub.4 R.sub.12, wherein X.sub.4 is oxygen or sulfur, and
R.sub.12 is alkyl of 1 to 3 carbon atoms or --(CH.sub.2).sub.2
NR.sub.15 R.sub.16, wherein R.sub.15 and R.sub.16 are the same or
different and are hydrogen or methyl;
(h) --CH.sub.2 X.sub.4 R.sub.13, wherein R.sub.13 is hydrogen or
alkyl of 1 to 3 carbon atoms, inclusive;
(i) 3-pyridyl;
(j) azetidino, pyrrolidino or piperidino;
(k) pyrrolidinomethyl;
(l) 4-methyl-1-piperazinyl; or
(m) c--N(CH.sub.2 CH.sub.2).sub.2 X.sub.4 ;
wherein
R.sub.11 is methyl or ethyl; and
wherein
X.sub.1 is oxygen or sulfur;
wherein
B is --CHR.sub.4 -- or --NH--, wherein R.sub.4 is hydrogen or
methyl;
wherein
R.sub.6 is
(a) phenyl;
(b) phenyl substituted at 1 or 2 positions with halogen, wherein,
if disubstituted, the substituents are the same or different;
or
(c) 2-pyridyl; and
wherein
R.sub.8 is hydrogen, halogen, or --X.sub.8 R.sub.81, wherein
X.sub.8 is sulfur, sulfinyl or sulfonyl and
R.sub.81 is alkyl of 1 to 3 carbon atoms; with the provisos
that
(i) R.sub.1 is C--N(CH.sub.2 CH.sub.2).sub.2 X.sub.4 and R.sub.6 is
phenyl only when R.sub.8 is other than hydrogen;
(ii) R.sub.1 is pyrrolidino only when R.sub.8 is other than bromo
or iodo;
(iii) R.sub.1 is methyl, B is CHR.sub.4 and R.sub.4 is hydrogen
only when
(a) R.sub.8 is other than --SR.sub.81, and
(b) R.sub.6 is other than phenyl, o-fluorophenyl,
2,5-difluorophenyl, 2-chloro-5-fluorophenyl, or o-chlorophenyl;
(iv) R.sub.1 is hydrogen, ethyl, n-propyl or isopropyl, and B is
--CHR.sub.4 ; or R.sub.1 is methyl, B is --CHR.sub.4, and R.sub.4
is methyl, only when
(a) R.sub.8 is other than --SR.sub.81, and
(b) R.sub.6 is other than phenyl; and
(v) R.sub.1 is n-butyl, n-pentyl, n-hexyl or isomers thereof only
when R.sub.8 is other than SR.sub.81 ; and
(vi) B is --NH-- only when
(a) A is --CR.sub.1 .dbd.N--,
(b) R.sub.1 is hydrogen or alkyl of 1 to 6 carbon atoms, and
(c) R.sub.6 is other than 2-pyridyl;
or a pharmacologically acceptable acid addition salt thereof,
effective to lower the mammal's systemic arterial blood pressure;
and further
(B) A compound of formula III
wherein
(1)-D-(2) is (1)--C(c--N(CH.sub.2 CH.sub.2).sub.2 S).dbd.N--(2),
(1)--C(c--N(CH.sub.2).sub.3).dbd.N--(2), or
(1)--C(.dbd.S)--NR.sub.111 -(2), wherein R.sub.111 is methyl or
ethyl;
wherein
R.sub.114 is hydrogen or methyl;
wherein
R.sub.116 is
(a) phenyl;
(b) phenyl substituted at 1 or 2 positions with halogen wherein, if
disubstituted, the substituents are the same or different; or
(c) 2-pyridyl; and
wherein R.sub.118 is hydrogen, halogen or --X.sub.9 R.sub.91,
wherein X.sub.9 is sulfur, sulfinyl, or sulfonyl and R.sub.91 is
alkyl of 1 to 3 carbon atoms; with the proviso that (1)-D-(1) is
(1)--C(c--N(CH.sub.2 CH.sub.2).sub.2 S).dbd.N--(2) and R.sub.116 is
phenyl only when R.sub.118 is other than hydrogen; or a
pharmacologically acceptable acid addition salt thereof;
(C) A compound of the formula I wherein (1)-A-(2) is (1)--CR.sub.1
.dbd.N--(2);
wherein
R.sub.1 is alkyl of 4 to 6 carbon atoms;
wherein
B is --NH--;
wherein
R.sub.6 is
(a) phenyl; and
(b) phenyl substituted at 1 or 2 positions with halogen,
wherein, if disubstituted, the substituents are the same or
different;
wherein R.sub.8 is hydrogen or halogen; or a pharmacologically
acceptable acid addition salt thereof.
"Alkyl of 1 to 3 carbon atoms" means methyl, ethyl, n-propyl or
isopropyl. "Alkyl of 4 to 6 carbon atoms" means n-butyl, n-pentyl,
n-hexyl or isomers thereof. "Alkyl of 1 to 6 carbon atoms" means
alkyl of 1 to 3 carbon atoms or alkyl of 4 to 6 carbon atoms.
"Halogen" means fluorine, chlorine, bromine or iodine.
Reference herein to a compound of formula I wherein R.sub.1 is
--CHX.sub.2 X.sub.3 and wherein X.sub.2 differs from X.sub.3
includes reference to each of the enantiomers of the compound.
Reference herein to "azetidino," "pyrrolidino," "piperidino,"
"morpholino," or "thiomorpholino" means that the moiety is linked
via a bond from its nitrogen atom to the carbon at position 1 of a
4H-s-triazolo[4,3-a][1,4]benzodiazepine moiety.
The compounds of concern for the present invention are either known
or can be prepared as described presently:
A. In all synthetic procedures described below, the starting
compound is of formula V, formula VI, or formula X wherein R.sub.8
and R.sub.6 are as described above for the compound of formula I,
R.sub.60 is any substituent within the scope of R.sub.6 except
2-pyridyl, and R.sub.10 is hydrogen or alkyl of 1 to 3 carbon
atoms. All compounds of formulas V, VI and X are known from the
disclosures of U.S. Pat. No. 3,422,091, U.S. Pat. No. 3,987,052,
and Fryer et al., J. Pharm. Sci. 53, 264 (1964) (for compounds of
formula V); U.S. Pat. Nos. 3,709,898 and 3,879,413 and references
cited therein (for compound of formula VI); and U.S. Pat. No.
4,082,764, Derieg et al., J. Org. Chem. 36, 782 (1971), and Hester,
J. Heterocyclic Chem. 17, 575 (1980) (for compounds of formula
X).
B. Using as starting material a compound of formula V, methods to
prepare:
(1) the corresponding compounds of formula I wherein (1)-A-(2) is
(1)--C(.dbd.O)--NR.sub.11 --(2) are known from the disclosure of
U.S. Pat. No. 3,646,055; see also Hester, Rudzik and
VonVoigtlander, J. Med. Chem. 23,402 (1980).
(2) the corresponding compounds of formula I wherein B is not
--NH-- and R.sub.1 is hydrogen or alkyl of 1 to 3 carbon atoms,
inclusive, including the compounds of formula VII, are known from
the disclosures of U.S. Pat. Nos. 3,987,052 and 3,734,922; the
compounds of formula I wherein (1)-A-(2) is (1)--CR.sub.1
.dbd.N--(2), R.sub.1 is alkyl of 4 to 6 carbon atoms, B is
--CHR.sub.4 --, R.sub.6 is other than 2-pyridyl, and R.sub.8 is
hydrogen, halogen, or --X.sub.8 R.sub.81 are known from the
disclosure of U.S. Pat. Nos. 3,880,877 and 3,882,101 and can be
made by the methods described therein or by methods known in the
art, for example by reacting a compound of the formula VIII with an
appropriate acid halide.
(3) the corresponding compounds of formula I wherein R.sub.1 is
3-pyridyl, --CH.sub.2 SR.sub.73, wherein R.sub.73 is alkyl or 1 to
3 carbon atoms, pyrrolidinomethyl, and cyanomethyl are known from
the disclosures of U.S. Pat. Nos. 3,734,922; 3,856,802; and
3,886,174;
(4) the corresponding compounds of formula I wherein R.sub.1 is
--CH.sub.2 X.sub.4 H or --CH.sub.2 OR.sub.73 are known from the
disclosure of Hester and VonVoigtlander (1979) cited above and
Belgian Pat. No. 782,680. To obtain the compound of formula I
wherein R.sub.1 is --CH.sub.2 SH, mercaptoacetic acid hydrazide is
reacted with the corresponding compound of formula V.
(5) the corresponding compounds of formula VIII are known from the
disclosures of Meguro and Kuwada, Chem. Pharm. Bull. 21, 2375
(1973); U.S. Pat. No. 3,751,426; and Hester, Rudzik and
VonVoigtlander, J. Med. Chem. 23, 392 (1980).
C. Using as starting material a compound of formula VI, the method
of preparing the corresponding compound of formula IX is known from
U.S. Pat. No. 3,709,898. In formula IX, R.sub.10 is hydrogen or
alkyl of one to 3 carbon atoms, inclusive. Using as starting
material a compound of formula X, the methods for preparing the
corresponding compounds of formula IX are known. Derieg et al., J.
Heterocyclic Chem. 8, 181 (1971); Meguro et al., Chem. Pharm. Bull.
21, 1619 (1973); Walser et al., J. Heterocyclic Chem. 12, 717
(1975); Hester, J. Heterocyclic Chem. 17, 575 (1980). Using
compounds of formula IX as starting material, methods to prepare
all corresponding compounds pertinent to the invention, including
those wherein B is --NH-- and those of formula VII wherein R.sub.6
is not phenyl, are known from U.S. Pat. Nos. 3,709,898; 3,879,413
and 3,891,666.
D. Using as starting material a compound of formula VII, methods to
prepare the corresponding compound of formula I wherein R.sub.1 is
chlorine, bromine, iodine, cyano, --O--R.sub.12,
--O(CH.sub.2).sub.2 NR.sub.15 R.sub.16, azetidino, pyrrolidino,
piperidino, 4-methyl-1-piperazinyl, morpholino, and thiomorpholino
are known from U.S. Pat. Nos. 3,709,899; 3,767,660; 3,894,025;
3,912,753 and 3,996,230. Preparations of the 1-iodo, 1-acetidino
and 1-thiomorpholino compounds are illustrated in Examples 1, 2 and
3 below.
E. Using as starting material a compound of formula VIII, methods
to prepare:
(1) the corresponding compounds of formula I wherein R.sub.1 is
trifluoromethyl are known from Hester and VonVoigtlander, cited
above;
(2) the corresponding compound of formula I wherein R.sub.1 is
--SR.sub.12 or S(CH.sub.2).sub.2 NR.sub.15 R.sub.16 are known from
Hester and VonVoigtlander, cited above, and U.S. Pat. Nos.
3,751,426 and 3,912,753;
(3) the corresponding compound of formula I wherein R.sub.1 is
cyanomethyl or --CHX.sub.2 X.sub.3 are known from U.S. Pat. No.
4,141,902.
An alternative procedure for preparing
8-alkylthio-4H-s-triazolo[4,3-a][1,4]benzodiazepines, except those
with halogen at the 1-position, is to first prepare a corresponding
8-halo analog, preferably the bromo or iodo, and then react the
8-halo analog with a corresponding alkali metal mercaptide,
MSR.sub.81, wherein M represents an alkali metal ion, preferably
that of sodium, in a solvent such as dimethylformamide,
dimethylsulfoxide or the like, preferably dimethylformamide.
A general summary of synthetic procedures for compounds of concern
in the present specification is provided by the Hester, Rudzik and
Kamdar (1971), Hester and VonVoigtlander (1979), Hester (1980) and
two Hester, Rudzik and VonVoigtlander (1980) references cited
above, as well as Hester, Chidester and Szmuszkovicz, J. Org. Chem.
44, 2688 (1979).
The preferred method for making compounds of formula II wherein
(1)-D-(2) is (1)--C(C--N(CH.sub.2 CH.sub.2).sub.2 S).dbd.N--(2) or
(1)--C(C--N(CH.sub.2).sub.3).dbd.N--(2), R.sub.116 is not 2-pyridyl
and R.sub.118 is not alkylthio is to synthesize the corresponding
1-bromo-4H-s-triazolo[4,3-a][1,4]benzodiazepine by bromination with
N-bromosuccinimide of the corresponding compound of formula VII,
which in turn is synthesized from the corresponding compound of
formula X by methods summarized in the Hester (1980) reference
cited above. The preferred method for making such compounds of
formula III wherein R.sub.118 is alkylthio is to synthesize the
corresponding 8-bromo analog by the preferred method starting from
the corresponding compound of formula X wherein R.sub.8 is bromine
and then use the alternative method provided above for making
8-alkylthio-4H-s-triazolo[4,3-a][1,4]benzodiazepines.
Compounds of formula III wherein (1)-D-(2) is
(1)--C(.dbd.S)--NR.sub.111 --(2) are synthesized starting with the
corresponding thione of formula V. The thione of formula V is
reacted in a known process with an alkylhydrazine to yield the
compound of formula XI. Hester, Chidester and Szmuszkovicz, J. Org.
Chem. 24, 2688 (1979). The resulting compound of formula XI is then
reacted with thiophosgene in a suitable solvent in the presence of
base to yield the desired compound of formula III. Suitable bases
are triethylamine or other organic amine bases, potassium or sodium
carbonate, and the like. Suitable solvents are dimethylformamide,
N,N-dimethylacetamide, methylene chloride, dioxane, tetrahydrofuran
and the like. Preferred is triethylamine as base in tetrahydrofuran
as solvent. See Hester and VonVoigtlander (1979), cited above,
wherein the synthesis of the 1-thiol (tautomer of the 1-thione)
from the compound of formula VIII by reaction with thiophosgene in
the presence of base is described.
Compounds of the formula I wherein (1)-A-(2) is (1)--CR.sub.1
.dbd.N--(2), R.sub.1 is alkyl of 4 to 6 carbon atoms, B is
CHR.sub.4, R.sub.6 is 2-pyridyl, and R.sub.8 is hydrogen or halogen
are prepared: (1) according to the method of U.S. Pat. No.
3,734,922 by reacting an appropriate compound of the formula V with
a hydrazide of the formula R.sub.1 --C(.dbd.O)--NH--NH.sub.2
wherein R.sub.1 is alkyl of 4 to 6 carbon atoms; or alternatively
by methods known in the art, for example by reacting an appropriate
compound of the formula VIII with an appropriate acid halide.
Compounds of the formula I wherein (1)-A-(2) is (1)--CR.sub.1
.dbd.N--(2), R.sub.1 is alkyl of 4 to 6 carbon atoms, B is --NH--,
R.sub.6 is (a) phenyl or (b) phenyl substituted at 1 or 2 positions
with halogen, and R.sub.8 is hydrogen or halogen are prepared
according to the method of U.S. Pat. No. 3,891,666.
A pharmacologically acceptable acid addition salt of the compounds
of formula I or formula III pertinent to the present invention can
be made by reacting the free bases of formula I or III with the
acid corresponding to the salt to be formed. The pharmacologically
acceptable acid addition salts contemplated for the present
invention include the hydrochlorides, hydrobromides, hydroiodides,
sulfates, nitrates, phosphates, acetates, propionates, palmitates,
benzoates, salicylates, hexynoates, phenylbutyrates, naphthoates,
glycolates, succinates, nicotinates, tartrates, maleates, malates,
pamoates, methanesulphonates, benzynesulfonates, toluenesulfonates,
cyclohexanesulfonates, picrates, citrates, lactates, and the
like.
Preferred compounds for use in the method of treatment disclosed
herein are those of formula I wherein R.sub.4 is hydrogen, R.sub.6
is phenyl, R.sub.8 is chloro, bromo or iodo and R.sub.1 is chloro,
bromo, iodo, morpholino, thiomorpholino, methylthio or methoxy, or,
in the case of the 1-ones or 1-thiones, R.sub.11 is methyl. More
preferred are the preferred compounds wherein R.sub.8 is chloro,
bromo or iodo and R.sub.1 is bromo, iodo or morpholino.
Most preferred are
8-bromo-6-phenyl-1-morpholino-4H-s-triazolo[4,3-a][1,4]benzodiazepine,
1,8-dibromo-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine, and
8-bromo-1-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
The preferred among the novel 1-thiomorpholino and 1-azetidino
compounds of the present invention are those of formula III wherein
R.sub.114 is hydrogen, R.sub.116 is phenyl and R.sub.118 is chloro,
bromo or iodo. Most preferred are the 8-bromo analogs of the
preferred compounds.
The preferred among the novel 1-thione compounds of the present
invention are those of formula III wherein R.sub.114 is hydrogen,
R.sub.116 is phenyl, R.sub.118 is chloro, bromo or iodo, and
R.sub.111 is methyl. Most preferred is the 8-bromo analog of the
preferred compounds.
Preferred among the novel compounds of the formula I of this
invention wherein (1)-A-(2) is (1)--CR.sub.1 .dbd.N--(2), and
R.sub.1 is alkyl of 4 to 6 carbon atoms are those wherein R.sub.1
is n-butyl and R.sub.8 is halogen. Most preferred is the 8-bromo
analog of the preferred compounds.
The method which comprises the present invention is to treat
hypertension in mammals suffering therefrom. The invention is
preferably applied to humans.
The skilled physician is able to ascertain by standard techniques
when a human is suffering from hypertension, a disease
characterized by a pathologically elevated, systemic arterial blood
pressure. Hypertension in a human is indicated by a diastolic blood
pressure (sitting) above about 85 mm Hg and a systolic blood
pressure (sitting) above about 120 mm Hg. Diastolic blood pressure
(sitting) above about 95 mm Hg and systolic blood pressure
(sitting) above about 140 mm Hg are especially indicative of
hypertension in a human.
The skilled veterinarian can ascertain when a non-human mammal is
suffering from hypertension, i.e. pathologically elevated, systemic
arterial blood pressure.
It is contemplated that, in carrying out the present invention, the
compounds to which it pertains will be administered by any suitable
route, including oral, parenteral, rectal, vaginal or transdermal.
Accordingly, the pharmaceutical forms contemplated for carrying out
the invention include pharmaceutical forms appropriate to these
routes of administration, including tablets, capsules, powders and
powder packets, cachets, dragees, solutions, suspensions, sterile
injectable forms, suppositories, bougies, suspensions in membranes
on tampons or other support means, and the like. In preparing these
forms, the active compounds may be combined with suitable,
pharmaceutically acceptable diluents or carriers such as
carbohydrates (e.g., lactose or sucrose), proteins, lipids, calcium
phosphate, cornstarch, stearic acid, methylcellulose, various oils
(e.g., coconut, sesame, safflower, cottonseed, peanut or corn),
water or aqueous solutions, or various polymeric membranes (e.g.,
polyvinylacetate films). Sweetening, coloring and flavoring agents
may be added to the various formulations or used to coat the
pharmaceutical forms.
The preferred route of administration is oral.
The method of treatment disclosed herein may be applied alone to
treat a mammal suffering from hypertension or may be employed
concomitantly or in conjunction with other methods for treating a
mammal suffering from the disease, such as administration of other
antihypertensive agents, dietary restrictions, and the like.
The dosage regimen for treating a mammal suffering from
hypertension by the method of the present invention is determined
in accordance with a variety of factors including the species, age,
weight, sex, medical condition and severity of the hypertension of
the mammal being treated, the particular compound or compounds
being employed, the route of administration of such compound or
compounds, and whether other methods for treating the mammal for
hypertension are also employed. A skilled physician or veterinarian
will readily ascertain and prescribe the correct amount of compound
to be administered in carrying out the method of the present
invention. In so doing, the physician or veternarian could employ
relatively low dosages at first and subsequently increase dosages
until the desired reduction in blood pressure is obtained.
For oral administration to a human, daily doses can vary from about
0.1 to about 1000 mg per day of active compound in carrying out the
method of the present invention. An equivalent dosage range for
administration by other suitable routes may also be employed.
EXAMPLE 1
8-Chloro-6-phenyl-1-thiomorpholino-4H-s-triazolo[4,3-a][1,4]benzodiazepine
A mixture of 2.0 gm (5.35 mmol) of
8-chloro-1-bromo-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine
and 2.0 ml of thiomorpholine was heated under nitrogen in an oil
bath at 120.degree. C. for 18 hr and then allowed to cool. The
reaction mixture was treated with methylene chloride and water. The
organic layer was separated, washed with dilute brine and
concentrated in vacuo. The residue was recrystallized from methanol
to yield 1.40 gm (72.7%) with m.p. 241.degree.-243.degree. C. and
0.46 gm (23.9%) with m.p. 239.degree.-241.degree. C. of the title
product. Analysis of the title product for carbon, hydrogen,
nitrogen, chlorine and sulphur revealed 60.47% C, 4.58% H, 18.03%
N, 9.14% Cl, and 8.09% S. Calculated values for such an analysis
for the title product are: 60.67% C, 4.58% H, 17.69% N, 8.98% Cl,
and 8.10% S.
Following the procedure of Example 1 but using as starting
material, instead of the
8-chloro-1-bromo-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine,
the 1,8-dibromo or 1-bromo-8-iodo analogs thereof,
8-bromo-6-phenyl-1-thiomorpholino-4H-s-triazolo[4,3-a][1,4]benzodiazepine
or
8-iodo-6-phenyl-1-thiomorpholino-4H-s-triazolo[4,3-a][1,4]benzodiazepine
a re obtained.
EXAMPLE 2
8-Bromo-1-iodo-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine
A stirred mixture of 0.339 gm (1 mmol) of
8-bromo-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine and 25 ml
of benzene was treated with 0.242 gm (1.1 mmol) of
N-iodosuccinimide and refluxed under nitrogen for 12 hr and 40 min.
The mixture was cooled and was then mixed with ice water containing
sodium bicarbonate and sodium chloride and was finally extracted
with methylene chloride. The extract was washed with dilute sodium
chloride, dried with sodium sulfate and concentrated in vacuo. The
residue was crystallized from methylene chloride-methanol to yield
one batch of 0.252 gm, which melted with decomposition between
209.degree. and 212.5.degree. C. and another batch of 0.020 gm
which melted with decomposition between 196.degree. and
198.5.degree. C. A portion of the first batch was recrystallized
twice by being dissolved in almost pure methylene chloride to which
methanol was slowly added during concentration. After this
recrystallization, the title product melted with decomposition
between 200.degree. and 207.degree. C. Another sample for analysis
was prepared by essentially the same procedure and, after
recrystallization from methylene chloride-methanol, molded with
decomposition between 216.degree. and 219.degree. C. Analysis of
the product for carbon, hydrogen and nitrogen showed C: 41.04%, H:
2.11%, N: 12.10%. Calculated values for such an analysis of the
product are: C: 41.31%; H: 2.16% and N: 12.05%.
EXAMPLE 3
8-chloro-6-phenyl-1-azetidino-4H-s-triazolo[4,3-a][1,4]benzodiazepine
0.20 gm of
1-bromo-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine
was mixed with 1.0 ml of trimethyleneimine and 0.09 gm of potassium
carbonate. The mixture was heated under N.sub.2 at 75.degree. C.
for 3.5 hours and then allowed to cool to room temperature. The
mixture was then poured into ice water. A solid precipitated, was
collected on a filter, washed twice with water, and dried in vacuo.
The solid was then recrystallized from ethylacetate to yield 0.12
gm of title product, m.p. 198.degree.-200.degree. C.
Following the procedure of example 3 but using as starting
material, instead of the
1-bromo-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine,
the 1,8-dibromo or 1-bromo-8-iodo analogs thereof,
8-bromo-6-phenyl-1-azetidino-4H-s-triazolo[4,3-a][1,4]benzodiazepine
or
8-iodo-6-phenyl-1-azetidino-4H-s-triazolo[4,3-a][1,4]benzodiazepine
are obtained.
EXAMPLE 4
8-Bromo-1-propyl-6-(2-pyridinyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepi
ne.
A mixture of 1.5 g of
7-bromo-2-hydrazino-5-(2-pyridinyl)-3H-1,4-benzodiazepine in 45 ml
of tetrahydrofuran cooled in an ice bath over a nitrogen atmosphere
is added 0.57 ml of butyryl chloride dropwise over 90 sec. After
stirring for 4.5 hrs, there is added an additional 0.1 ml of
butyryl chloride. The resulting mixture is then stirred at ambient
temperature for 18 hrs, poured into 300 ml of aqueous sodium
bicarbonate and filtered. The filtrate is extracted with
dichloromethane, washed with dilute brine, dried over sodium
sulphate, and concentrated under reduced pressure. The resulting
residue is then heated in an oil bath at 120.degree.-125.degree. C.
for 45 min, allowed to cool, and concentrated under reduced
pressure. The residue is then dissolved in dichloromethane, washed
with aqueous sodium bicarbonate and dilute brine, dried over sodium
sulphate, and concentrated under reduced pressure. The resulting
residue is then chromatographed on 150 g of silica gel eluting with
2.5% methanol in dichloromethane. Crystallization from ethyl
acetate yields 0.27 g of title product. Melting point is
184.degree.-186.degree. C.
EXAMPLE 5
8-Bromo-1-butyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine.
To a solution of 2 g of
7-bromo-2-hydrazino-5-phenyl-3H-[1,4]benzodiazepine in 60 ml of
tetrahydrofuran cooled in an ice bath under a nitrogen atmosphere
is added 0.87 ml of valeryl chloride dropwise over 3 min. After
stirring for 2.5 hrs, the reaction mixture is then poured into 100
ml of water and aqueous sodium bicarbonate. A solid precipitate is
then collected on a filter, washed with water and dried. The
resulting residue is then dissolved in 25 ml of acetic acid, heated
under a nitrogen atmosphere in an oil bath to 125.degree. C. for 35
min, allowed to cool, and concentrated under reduced pressure.
Crystallization of the residue from a mixture of methanol and water
yields 0.88 g of title product with melting point
87.degree.-90.degree. C. and 0.41 g of title product with melting
point 88.degree.-90.degree. C. as a monohydrate.
EXAMPLE 6
8-Bromo-1-(2,2-dimethylpropyl)-6-phenyl-4H-[
1,2,4]triazolo[4,3-a][1,4]benzodiazepine.
Following the procedure of Example 5, 2.0 g of
7-bromo-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine is reacted with
1.01 ml of tert-butyl acetylchloride to yield 1.17 g of title
product with melting point 229.5.degree.-232.degree. C. and 0.30 g
of title product with melting point 205.degree.-219.degree. C.
EXAMPLE 7
8-Bromo-1-(2-methylpropyl)-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiaz
epine.
Following the procedure of Example 5, 2.5 g of
7-bromo-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine and 1.11 ml of
isovaleryl chloride is transformed to 1.03 g of title product with
melting point 93.degree.-95.degree. C.
EXAMPLE 8
The hypotensive activity of compounds pertinent to the present
invention was determined by tests on rats and
baroreceptor-denervated cats:
A. Tests on Rats
Female Sprague-Dawley rats weighing 200-250 gm were fasted for
22-28 hours prior to anesthesia by intravenous (tail vein)
administration of 8 ml/kg of a 5% glucose solution containing 5
mg/ml of .alpha.-chloralose, 5 mg/ml of urethane and 1.87 mg/ml of
sodium pentobarbital.
Thirty minutes after anesthesia, the right external jugular vein
and left common carotid artery were cannulated with PE-50
catheters, which had been pre-filled with 0.2 ml of 20 units/ml of
heparanized saline.
Arterial pressures were continuously recorded through the arterial
cannula with a Statham P23Gc transducer and Grass Model 7
polygraph.
All substances administered intravenously were administered through
the venous cannula. Every intravenous administration of test
compound of vehicle (N,N-dimethylacetamide) was followed by a rinse
with 0.2 ml of 20 units/ml of heparanized saline.
The rats were affixed prone to test tube racks, one rat per rack,
with 0 silk ligatures in their loose axillary skin. The racks were
variably heated by passing warm water, at variable temperature and
flow rate, through vinyl tubing passing through the racks. The rats
were covered with aluminum foil domes and the heating was varied to
maintain the rats' rectal temperatures between 34.degree. and
37.degree. C.
Sometime after the rats had been affixed to the racks and 90
minutes after administration of anesthetic, a 20 minute
pre-treatment period was begun. During this period, the rats'
arterial pressures stabilized to base-line values.
Following the 20 minute pre-treatment period, rats were dosed
intravenously with vehicle alone (0.19 ml/kg of
N,N-dimethylacetamide) as control or a test compound in vehicle.
Vehicle control or test compound (dissolved in
N,N-dimethylacetamide so that, to achieve the desired dose, 0.19
ml/kg of solution had to be administered) was administered
cumulatively according to the following schedule:
______________________________________ DOSE Test Compound (in 0.19
ml of TIME Vehicle Alone solution in (Post-treatment) (control)
vehicle) min. ml/kg mg/kg ______________________________________ 0
0.19 0.03 20 0.19 0.3 40 0.19 3.0
______________________________________
For vehicle alone and each test compound, the procedure was applied
to a group of at least four rats. For each such group, all rats
were subjected to the procedure together, but the procedures
started on individual rats 5-7 minutes apart.
For each rat, arterial pressures at 0 minute (just before first
administration of vehicle or test compound), 20 minutes
post-treatment (just before second administration of vehicle or
test compound), 40 minutes post-treatment (just before third
administration of vehicle or test compound), and 60 minutes
post-treatment were determined. Thus, for each rat, the differences
in arterial pressure at 20, 40, or 60 minutes post-treatment from
that at 0 minutes could be determined. For each test compound and
the vehicle alone as control, the average of each of these
differences for all rats in the test or control group was
determined. It is these averages, mean arterial pressure (MAP)
changes, which were taken as the measure of the blood
pressure-lowering effect of test compound (in vehicle) or vehicle
alone and which are entered under "MAP Change" in Table A
below.
Essentially the same procedure was applied with minoxidil
(2,4-diamino-6-piperidinopyrimidine-3-oxide), a compound known to
be an antihypertensive agent in humans. At post-treatment time 0, 3
to 5 mg/kg of minoxidil in 0.1M citric acid as vehicle (1.0 ml/kg
dose volume) was administered to the rats. At 15 minutes
post-treatment, the arterial blood pressure of the rats was reduced
16.+-.2 mm Hg, and at 30 minutes post-treatment their arterial
blood pressure was reduced 19.+-.3 mm Hg. In control rats, at
post-treatment time 0 administered 1 ml/kg of 0.1M citric acid,
arterial blood pressure was reduced 4.+-.1 mm Hg at 15 minutes and
6.+-.1 mm Hg at 30 minutes post-treatment.
The procedure was also applied with clonidine
(2-(2,6-dichloroanilino)-2-imidazoline), also a compound known to
be an hypotensive agent in humans. At post-treatment time 0, 0.015
mg/kg of clonidine was administered in 0.9% sodium chloride as
vehicle (0.5 ml/kg dose volume). At 15 minutes post-treatment, the
arterial blood pressure of the rats was reduced 24.+-.6 mm Hg, and
at 30 minutes post-treatment their blood pressures were reduced
28.+-.5 mm Hg. The aqueous sodium chloride vehicle alone was found
to have no effect on the rats' blood pressure.
TABLE A ______________________________________ MAP change Compound
of Formula I (mm/Hg) at ______________________________________ B is
--CH.sub.2 --, plus plus A is --CR.sub.1 .dbd.N-- 0.03 0.3 3.0
R.sub.1 R.sub.6 R.sub.8 mg/kg mg/kg mg/kg
______________________________________ morpholino phenyl Cl -10 -13
-22 morpholino phenyl Br -7 -14 -23 morpholino o-chloro- Cl -6 -17
-19 phenyl H 2-pyridyl Br -1 -14 -22 CH.sub.3 S phenyl Br -6 -14
-26 I phenyl Br -2 -11 -20 Br phenyl Cl -8 -18 -28 Br phenyl Br -9
-18 -28 Cl phenyl Br.sup. 1 -12 -17 -26 pyrrolidino phenyl Cl -6
-14 -27 3-pyridyl phenyl Cl -9 -13 -26 thiomorpholino phenyl Cl -5
- 6 -18 morpholino phenyl --SCH.sub.3.sup.1 -3 - 6 -17
______________________________________ B is --CH.sub. 2 --, A is
--C(.dbd.O)--NR.sub.11 --: R.sub.11 R.sub.6 R.sub.8
______________________________________ CH.sub.3 phenyl Cl -6 -11
-21 ______________________________________ B is --NH--: R.sub.1
R.sub.6 R.sub.8 ______________________________________ CH.sub.3
phenyl Cl -4 -9 -16 plus plus plus 0.19 0.19 0.19 ml/kg ml/kg ml/kg
Control (N,N--dimethylacetamide) -5 -6 - 7
______________________________________ .sup.1 Compound tested on 3
rats
B. Tests on Baroreceptor-denervated Cats
Compounds were tested for hypotensive activity in the
baroreceptor-denervated cat. See, e.g., McCall et al., Europ. J.
Pharmacol. 36, 69 (1976); McCall et al., J. Auton. Nerv. Sys. 3, 9
(1981).
Except as noted herein, the details of the procedure used are
provided in the McCall et al. 1981 reference cited above.
Cats were anesthetized by i.p. injection of a mixture of diallyl
barbiturate (60 mg/kg), urethane (240 mg/kg) and monoethylurea (240
mg/kg). The cats were then placed in a stereotaxic apparatus and
were artificially respired with a Harvard respirator (50
cc.times.12 cpm). Arterial pressure was measured directly from a
femoral artery cannula with a Statham transducer and a Grass
polygraph. The cats were baroreceptor denervated by bilaterally
sectioning the carotid sinus nerves, the vagi, and the aortic
depressor nerves after everting the trachea and esophagus into the
mouth. The external carotid nerve was isolated at its juncture with
the superior cervical ganglion for monophasic recording of
sympathetic discharges under oil with a platinum electrode.
Acceptable nerve activity was not considered a prerequisite for
inclusion into the study.
The cats were allowed to stabilize for a minimum of one hour
following baroreceptor-denervation. After a 5-10 minute
pre-treatment period, the cats were dosed intravenously with 0.03
mg/kg of a test compound. Subsequent to this initial dose, the drug
was supplemented in a progressive, incremental fashion to total
intravenous doses of 0.1, 0.3, 1.0, and 3.0 mg/kg at 30 minute
intervals. The drug concentration for the first two dosages (0.03
mg/kg and 0.07 mg/kg) was 3.0 mg/ml in vehicle
(N,N-dimethylacetamide). The drug concentration for the last three
dosages (0.2 mg/kg, 0.7 mg/kg and 2.0 mg/kg) was 30.0 mg/ml in
vehicle. Similarly prepared, untreated control cats received the
vehicle alone in the following dosages: 0.01 ml/kg at
post-treatment time 0, 0.023 ml/kg at post-treatment time 30
minutes, 0.007 ml/kg at post-treatment time one hour, 0.023 ml/kg
at post-treatment time 1.5 hour, and 0.067 ml/kg at post-treatment
time 2 hours.
Arterial pressure and integrated sympathetic nerve activity (SNA)
were determined at 30 minutes after each administration of test
compound or vehicle alone, just before a subsequent administration,
if any, of test compound or vehicle.
Each mean arterial pressure change (MAP Change) reported in Table B
is the average, for all cats in the group involved, of the
differences between the arterial pressure at the time of
measurement and that at post-treatment time 0. Similarly, each SNA
reported in the Table is the average, for all cats in the group
involved, of the percentage of activity at the time of measurement
relative to that at post-treatment time 0.
TABLE B
__________________________________________________________________________
MAP SNA (Relative to Compound of Formula I Dose Change
post-treatment R.sub.1 R.sub.4 R.sub.6 R.sub.8 N.sup.1 (Cumulative)
mm Hg time O, mean) %
__________________________________________________________________________
mg/kg morpholino H phenyl Cl 4 0.03 -29 -34 0.1 -26 -50 0.3 -34 -56
1.0 -47 -63 3.0 -51 -73 morpholino CH.sub.3 phenyl Cl 5 0.03 ND ND
0.1 ND ND 0.3 -11 -34 1.0 -27 -60 3.0 -48 -35 morpholino H o- Cl 2
0.03 +2 -35 chloro 0.1 -28 -54 phenyl 0.3 -29 -35 1.0 -34 -49 3.0
-29 -53 morpholino H phenyl Br 7 0.03 -4 -4 0.1 -17 -32 0.3 -23 -53
1.0 -41 -72 3.0 -42 -75 8-chloro-1-methyl-4H--s- 2 0.03 -3 ND
triazolo[4,3-a][1,3,4]- 0.1 -5 ND benzotriazepine 0.3 -7 -40 1.0
-14 ND 3.0 -15 -24 ml/kg Vehicle (N,N--dimethyl 7 0.01 +6 0
acetamide) 0.033 +6 +15 0.04 +6 +24 0.063 +4 +35 0.13 +3 +34
__________________________________________________________________________
.sup.1 Number of cats used in test of compound ND = not determined
##STR1##
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